Abstract
STIM1 and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease.
Highlights
stromal interaction molecule1 (STIM1) and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current
The significance of Store-operated calcium entry (SOCE) is highlighted by diverse mutations in STIM1 and Orai1 genes, which result in Ca2+-release activated Ca2+(CRAC) channelopathies that are characterized by autoimmunity, immunodeficiency, skeletal myopathy, and ectodermal dysplasia6,12–18
In an attempt to initially characterize the function of the Stormorken-related STIM1 R304W, we co-overexpressed YFPOrai1 and CFP-STIM1 R304W in HEK293 cells for electrophysiological recordings
Summary
STIM1 and Orai are key components of the Ca2+-release activated Ca2+ (CRAC) current. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1 This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease. CAD/SOAR exposure is triggered upon ER store depletion, releasing the CC1–CC3 clamp, switching the cytosolic portion of STIM1 from a tight into an extended conformation. Our data suggest that a localized helical extension of the CC1α2–CC1α3 linker within the CC1 domain together with increased homomerization propensity induced by the R304W mutation switches STIM1 into the extended, activated conformation This dual mechanism is distinct from other mutations in the initial portion of the CC1 domain that directly weaken the CC1–CC3 clamp when inducing STIM1 into a similar extended, active state. The rigidity of CC1α2–CC1α3 linker of wild-type STIM1 is fine-tuned for physiological signaling by enabling a STIM1 homomerization propensity and SOAR/CAD exposure precisely situated between constitutive and significantly slowed store-dependent activation
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